Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.
Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.
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DOI：
10.1038/leu.2016.393
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发表时间：
2017-09
期刊：
影响因子：
11.4
通讯作者：
Bhalla KN
中科院分区：
文献类型：
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作者：
Saenz DT;Fiskus W;Qian Y;Manshouri T;Rajapakshe K;Raina K;Coleman KG;Crew AP;Shen A;Mill CP;Sun B;Qiu P;Kadia TM;Pemmaraju N;DiNardo C;Kim MS;Nowak AJ;Coarfa C;Crews CM;Verstovsek S;Bhalla KN
protac（涉及蛋白水解的嵌合体）ARV-825招募了溴结构域和外影响（BET）蛋白质到E3泛素连接酶的小酶Cereblon，从而导致BET蛋白降解，而包括BET蛋白（BETI）OTX01154。 ，用等摩尔浓度的ARV-825治疗导致BRD4的持续且持续的耗竭（> 90％），并在培养的和患者衍生的（PD）CD34+ MPN SAML细胞，同时占CD34+正常造血祖细胞的相对较高的RNA-Seq，反向相位蛋白质阵列和质量细胞仪的分析表明，ARV-825在MRNA和蛋白质中造成了更大的扰动与otx015相比，SAML细胞中的otx015比ARV-825的表达与OTX015相比与表达荧光素酶的HEL92.1.7细胞的小鼠与ARV-825共同治疗。 PD-CD34+ SAML细胞，尤其是ARV-825在体外产生的鲁u属尼替尼或ruxolitinib耐药的SAML细胞中诱导高水平的凋亡。 SAML。
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reversed Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in mRNA and protein expressions than OTX015 in sAML cells. Specifically, compared to OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, pSTAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared to OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against the established and PD-CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.
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DOI：
10.1158/1078-0432.ccr-11-1541
发表时间：
2011-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Fiskus W;Verstovsek S;Manshouri T;Rao R;Balusu R;Venkannagari S;Rao NN;Ha K;Smith JE;Hembruff SL;Abhyankar S;McGuirk J;Bhalla KN
通讯作者：
Bhalla KN
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.7
作者：
Fiskus, Warren;Verstovsek, Srdan;Bhalla, Kapil N.
通讯作者：
Bhalla, Kapil N.
DOI：
10.1200/edbook_am.2013.33.301
发表时间：
2013-01-01
期刊：
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
影响因子：
--
作者：
Keohane, Clodagh;Mesa, Ruben;Harrison, Claire
通讯作者：
Harrison, Claire